Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis

Abstract

BACKGROUND Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. RESULTS Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. CONCLUSIONS The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)

The role of moxifloxacin in tuberculosis therapy

“…In 2014, three trials were reported that relate to treatment shortening based on the substitution of a fluoroquinolone [9][10][11].…”

“…The important approach to TB drug development that can yield results rapidly is to repurpose drugs that also have activity against TB. Moxifloxacin is an example of this process and will be the focus of this review, which is timely as the results of three phase III clinical trials utilising a fluoroquinolone as a key component in the treatment of susceptible infection have been reported recently [9][10][11] and novel moxifloxacin regimens for the treatment of MDR disease are in progress [12]. Moxifloxacin also has an important role in the management of patients who are unable to tolerate a …”

Methodological considerations in clinical trials for new MDR-TB treatment regimens

“…It is known that the majority of relapses occur within six months of stopping treatment in clinical trials of DS-TB (18,19) and results from REMoxTB (20), RIFAQUIN(21) and OFLOTUB (22) have confirmed this. Some groups are therefore designing clinical trials in DS-TB with the primary endpoint 12 months after randomisation (i.e.…”

The implications of model-informed drug discovery and development for tuberculosis

“…The disappointing results from all recent Phase III trials of TB drugs [2][3][4][5] clearly demonstrate that a shift in paradigm is needed in TB drug development. Insufficient efficacy is the main cause for failures in clinical drug development [6,7].…”